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Synthesis of an isotopically labeled naphthalene derivative that supports a long-lived nuclear singlet state.

ABSTRACT: The synthesis of an octa-alkoxy substituted isotopically labeled naphthalene derivative, shown to have excellent properties in singlet NMR experiments, is described. This highly substituted naphthalene system, which incorporates an adjacent (13)C spin pair, is readily accessed from a commercially available (13)C2-labeled building block via sequential thermal alkynyl- and arylcyclobutenone rearrangements. The synthetic route incorporates a simple desymmetrization approach leading to a small difference in the chemical shifts of the (13)C spin pair, a design constraint crucial for accessing nuclear singlet order.

SUBMITTER: Hill-Cousins JT

PROVIDER: S-EPMC4516318 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Nuclear singlet multimers (NUSIMERs) with long-lived singlet states.

Project description:Magnetic resonance (NMR) is a powerful tool in chemical analysis, structure determination and in medical diagnostics. Developing novel biological sensors for this field holds promise to better investigate protein structures or target diseases more efficiently. Herein, we explore nuclear spin singlet states in dendritic macromolecules as a platform molecule to develop stimuli responsive probes. We have developed a nuclear singlet multimer (NUSIMER) based on a generation 5 poly(amidoamine) dendrimer (PAMAM) which contains on average about 90 accessible nuclear spin singlet states with lifetimes up to 10-fold longer than the T 1 relaxation times (up to 10 seconds T s vs. T 1 < 0.5 seconds) in a single molecule. We demonstrate little influence on the singlet lifetime in phosphate buffer (H2O) and a high viscosity gel environment in the presence of paramagnetic oxygen. Additionally, we demonstrate an increase in singlet lifetime upon the release of a protective chemical moiety from the NUSIMER following a stimulus, whereby no change in longitudinal relaxation time is observed. The robustness and change in singlet lifetime of the NUSIMER holds promise for the development of a novel type of biosensors.

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Enantioselective synthesis of isotopically labeled homocitric acid lactone.

Project description:A concise synthesis of homocitric acid lactone was developed to accommodate systematic placement of carbon isotopes (specifically (13)C) for detailed studies of this cofactor. This new route uses a chiral allylic alcohol, available in multigram quantities from enzymatic resolution, as a starting material, which transposes asymmetry through an Ireland-Claisen rearrangement.

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Chemo-enzymatic synthesis of isotopically labeled nicotinamide riboside.

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Unlocking a Diazirine Long-Lived Nuclear Singlet State via Photochemistry: NMR Detection and Lifetime of an Unstabilized Diazo-Compound.

Project description:Diazirines are important for photoaffinity labeling, and their photoisomerization is relatively well-known. This work shows how hyperpolarized NMR spectroscopy can be used to characterize an unstable diazo-compound formed via photoisomerization of a 15N2-labeled silyl-ether-substituted diazirine. This diazirine is prepared in a nuclear spin singlet state via catalytic transfer of spin order from para-hydrogen. The active hyperpolarization catalyst is characterized to provide insight into the mechanism. The photochemical isomerization of the diazirine into the diazo-analogue allows the NMR invisible nuclear singlet state of the parent compound to be probed. The identity of the diazo-species is confirmed by trapping with N-phenyl maleimide via a cycloaddition reaction to afford bicyclic pyrazolines that also show singlet state character. The presence of singlet states in the diazirine and the diazo-compound is validated by comparison of experimental nutation behavior with theoretical simulation. The magnetic state lifetime of the diazo-compound is determined as 12 ± 1 s in CD3OD solution at room temperature, whereas its chemical lifetime is measured as 100 ± 5 s by related hyperpolarized NMR studies. Indirect evidence for the generation of the photoproduct para-N2 is presented.

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Synthesis of isotopically labeled P-site substrates for the ribosomal peptidyl transferase reaction.

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Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications.

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Design and synthesis of a novel ZB716-d6 as a stable isotopically labeled internal standard.

Project description:ZB716 is a synthetic, steroidal, orally active anti-estrogen agent that is under clinical development for the treatment of estrogen receptor (ER)-positive metastatic breast cancer. The stable isotope-labeled ZB716 was required for use as an internal standard in LC-MS/MS assays. Therefore, a novel deuterated ZB716 (ZB716-d6) as an isotopically labeled internal standard was designed and synthesized through a newly developed route, which prepared ZB716-d6 in eight steps from the commercially available deuterium-labeled starting material [2H6]pentafluoropentanol. This procedure is very practicable and gives the final compound in good yield (19% total yield) and high purity (D, >99%, chemical purity 98%). At present, ZB716-d6 has been successfully used as an internal standard in clinical bioanalysis.

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Excited State Vibrations of Isotopically Labeled FMN Free and Bound to a Light-Oxygen-Voltage (LOV) Protein.

Project description:Flavoproteins are important blue light sensors in photobiology and play a key role in optogenetics. The characterization of their excited state structure and dynamics is thus an important objective. Here, we present a detailed study of excited state vibrational spectra of flavin mononucleotide (FMN), in solution and bound to the LOV-2 (Light-Oxygen-Voltage) domain of Avena sativa phototropin. Vibrational frequencies are determined for the optically excited singlet state and the reactive triplet state, through resonant ultrafast femtosecond stimulated Raman spectroscopy (FSRS). To assign the observed spectra, vibrational frequencies of the excited states are calculated using density functional theory, and both measurement and theory are applied to four different isotopologues of FMN. Excited state mode assignments are refined in both states, and their sensitivity to deuteration and protein environment are investigated. We show that resonant FSRS provides a useful tool for characterizing photoactive flavoproteins and is able to highlight chromophore localized modes and to record hydrogen/deuterium exchange.

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Chemoenzymatic Semi-synthesis Enables Efficient Production of Isotopically Labeled α-Synuclein with Site-Specific Tyrosine Phosphorylation.

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Tracking isotopically labeled oxidants using boronate-based redox probes.

Project description:Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18-labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

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